What are the management and treatment options for lactic acidosis associated with Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide)?

Management of Lactic Acidosis Associated with Biktarvy

Immediately discontinue Biktarvy if lactic acidosis is suspected or confirmed, as this is the most critical intervention to prevent mortality. 1, 2, 3

Understanding Biktarvy-Associated Lactic Acidosis

Biktarvy contains emtricitabine and tenofovir alafenamide (TAF), both nucleoside reverse transcriptase inhibitors (NRTIs) that can cause lactic acidosis through mitochondrial toxicity. 4, 5 While TAF has significantly lower mitochondrial toxicity compared to older NRTIs like stavudine and didanosine, lactic acidosis remains a rare but potentially fatal complication. 4, 6

Mechanism of Toxicity

• NRTIs inhibit DNA polymerase γ, the enzyme responsible for mitochondrial DNA synthesis, leading to impaired cellular energy production and increased anaerobic metabolism with lactate accumulation. 4
• TAF has lower potential for mitochondrial toxicity than older NRTIs, but cases of severe lactic acidosis have been documented, particularly with inappropriate dosing or in patients with risk factors. 4, 5, 6

Clinical Recognition and Diagnosis

Lactate Thresholds and Interpretation

• Lactate 2-5 mmol/L: Elevated, requires correlation with symptoms and close monitoring 1
• Lactate >5 mmol/L: Abnormal, indicates serious toxicity 1, 7
• Lactate >10 mmol/L: Life-threatening situation requiring immediate intensive intervention 1

Clinical Presentation

Early symptoms are often nonspecific and should not be ignored: 1, 7

• Gastrointestinal symptoms: nausea, vomiting, anorexia, abdominal pain 1
• Respiratory symptoms: dyspnea, tachypnea (indicating respiratory compensation) 1, 7
• Systemic symptoms: generalized weakness, fatigue, myalgias, weight loss 1
• Hepatomegaly may be present with hepatic steatosis 1

Laboratory Evaluation

Essential initial tests: 1, 7

• Serum lactate (using proper collection technique: prechilled fluoride-oxalate tubes, transported on ice, processed within 4 hours, collected without tourniquet or fist-clenching) 1
• Arterial blood gas with pH and bicarbonate 7
• Anion gap calculation: Na − [Cl+CO₂] (>16 indicates lactic acidosis) 1, 7
• Complete metabolic panel including liver enzymes (AST, ALT, LDH) 1
• Creatine phosphokinase, lipase, amylase 1
• Renal function (creatinine, eGFR) 3, 8

Imaging considerations: 1

• Abdominal ultrasound or CT may reveal hepatomegaly with fatty infiltration 1
• Liver biopsy may show microvesicular steatosis if diagnosis is uncertain 1, 9

Immediate Management Algorithm

Step 1: Discontinue Biktarvy Immediately

This is the single most important intervention. 1, 2, 3, 5

• Do not wait for confirmatory testing if clinical suspicion is high 1
• Antiretroviral treatment should be suspended if clinical and laboratory manifestations of lactic acidosis syndrome occur 1

Step 2: Intensive Supportive Care

For severe lactic acidosis (lactate >5 mmol/L or pH <7.3): 1, 7

• Fluid resuscitation: Restore tissue perfusion with isotonic crystalloids (15-20 mL/kg/h initially if shock present) 7
• Bicarbonate therapy: Consider bicarbonate infusions for severe acidosis, though efficacy is debated and should NOT be used if pH ≥7.15 1, 7, 10
• Hemodialysis: Indicated for refractory lactic acidosis, particularly if concurrent renal failure 1, 8
• Continuous renal replacement therapy (CRRT): May be necessary for persistent acidosis despite other interventions 8, 6
• Mechanical ventilation: Required if respiratory failure develops from tachypnea and dyspnea 1

Step 3: Adjunctive Therapies

Consider cofactor supplementation (though efficacy requires clinical validation): 1

• Thiamine supplementation (addresses potential pyruvate dehydrogenase dysfunction) 1, 7
• Riboflavin (based on pathophysiologic hypothesis of mitochondrial respiratory chain dysfunction) 1, 11

Step 4: Monitor Serial Lactate Levels

• Repeat lactate every 2-6 hours during acute resuscitation 7, 10
• Target lactate clearance of at least 10% every 2 hours during first 8 hours 10
• Normalization within 24 hours is associated with improved survival 10

Risk Factors and Prevention

High-Risk Populations Requiring Closer Monitoring

• Female gender (higher risk for severe lactic acidosis) 4
• Obesity 4, 9
• Low body weight/underweight patients (risk of elevated drug concentrations) 9
• Pregnancy 4
• Prolonged NRTI use 4
• Renal impairment (requires dose adjustment; TAF accumulation can occur) 2, 3, 8, 9
• Hepatic impairment (impaired lactate clearance) 7
• Concomitant nephrotoxic medications 3
• Inappropriate dosing (higher than recommended doses significantly increase risk) 5

Monitoring Recommendations

Prior to initiating Biktarvy: 3

• Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein 3
• In patients with chronic kidney disease, also assess serum phosphorus 3

During treatment: 1, 3

• Monitor serum bicarbonate and electrolytes every 3 months for early identification of increased anion gap 1
• Assess renal function on a clinically appropriate schedule 3
• Maintain high clinical suspicion for early symptoms of mitochondrial toxicity 1, 7

Dose Adjustments for Renal Impairment

Emtricitabine dosing: 2

• CrCl ≥50 mL/min: 200 mg every 24 hours
• CrCl 30-49 mL/min: 200 mg every 48 hours
• CrCl 15-29 mL/min: 200 mg every 72 hours
• CrCl <15 mL/min or hemodialysis: 200 mg every 96 hours (give after dialysis on dialysis days)

Tenofovir alafenamide: 3

• No dosage adjustment required for CrCl ≥15 mL/min or ESRD on chronic hemodialysis
• Administer after hemodialysis on dialysis days
• Not recommended in ESRD patients not receiving chronic hemodialysis

Restarting Antiretroviral Therapy

After resolution of lactic acidosis: 1

• Some patients tolerate reintroduction of NRTI-containing regimens after discontinuation 1
• However, insufficient data exist to recommend this strategy versus NRTI-sparing regimens 1
• Consider switching to antiretrovirals with lower mitochondrial toxicity potential (e.g., integrase inhibitors without NRTIs) 4
• If NRTIs are reintroduced, progressive mitochondrial toxicity can recur, producing severe lactic acidosis 1

Critical Pitfalls to Avoid

• Do not ignore nonspecific early symptoms (nausea, fatigue, dyspnea) in patients on Biktarvy—these often precede severe acidosis 1, 7
• Do not delay discontinuation of Biktarvy while awaiting confirmatory testing if clinical suspicion is high 1
• Do not use sodium bicarbonate for pH ≥7.15—it does not improve outcomes and may cause harm 7, 10
• Do not overlook drug-drug interactions that may increase tenofovir levels (e.g., cobicistat) 9
• Do not miss inappropriate dosing as a cause of toxicity 5
• Do not restart the same NRTI regimen without careful consideration of alternative antiretroviral strategies 1, 4

Special Considerations

Hepatitis B Coinfection

• Severe acute exacerbations of hepatitis B can occur after discontinuing emtricitabine or tenofovir 2, 3
• Monitor closely with clinical and laboratory follow-up for at least several months after stopping treatment 2, 3
• Initiation of alternative anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis 2, 3

Concomitant Metformin Use

• The combination of metformin and tenofovir significantly increases lactic acidosis risk, particularly with renal impairment 8
• Consider discontinuing metformin if lactic acidosis develops 7, 8